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Epigenetic silencing of myogenic gene program by Myb-binding protein 1a suppresses myogenesis.

ABSTRACT: Skeletal myogenesis involves highly coordinated steps that integrate developmental cues at the chromatin of muscle progenitors. Here, we identify Myb-binding protein 1a (Mybbp1a) as a novel negative regulator of muscle-specific gene expression and myoblast differentiation. The mode of action of Mybbp1a was linked to promoter regulation as illustrated by its interaction with MyoD at the genomic regions of silent muscle-specific genes as well as its negative effect on MyoD-mediated transcriptional activity. We propose that Mybbp1a exerts its repressive role by inducing a less permissible chromatin structure following recruitment of negative epigenetic modifiers such as HDAC1/2 and Suv39h1. At the onset of differentiation, Mybbp1a undergoes a promoter disengagement that may be due to the differentiation-responsive, miR-546-mediated downregulation of Mybbp1a expression. Moreover, such alteration gave rise to promoter enrichment of activators and histone acetylation, an epigenetic status amenable to gene activation. Together, these findings unveil a hitherto unrecognized transcriptional co-repressor role of Mybbp1a in proliferating muscle progenitor cells, and highlight an epigenetic mechanism by which Mybbp1a and miR-546 interplay to control myoblast differentiation transition.

SUBMITTER: Yang CC

PROVIDER: S-EPMC3321204 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Epigenetic silencing of myogenic gene program by Myb-binding protein 1a suppresses myogenesis.

Yang Chang-Ching CC Liu Hsuan H Chen Shen Liang SL Wang Tzu-Hao TH Hsieh Chia-Ling CL Huang Yi Y Chen Shu-Jen SJ Chen Hua-Chien HC Yung Benjamin Yat-Ming BY Chin-Ming Tan Bertrand B

The EMBO journal 20120214 7

Skeletal myogenesis involves highly coordinated steps that integrate developmental cues at the chromatin of muscle progenitors. Here, we identify Myb-binding protein 1a (Mybbp1a) as a novel negative regulator of muscle-specific gene expression and myoblast differentiation. The mode of action of Mybbp1a was linked to promoter regulation as illustrated by its interaction with MyoD at the genomic regions of silent muscle-specific genes as well as its negative effect on MyoD-mediated transcriptional ...[more]

PMID: 22333916

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Project description:ObjectivesThe present study sought to investigate the mechanisms underlying the mitogenic function of telomerase and to test the hypothesis that everolimus, commonly used on drug-eluting stents, suppresses smooth muscle cells (SMC) proliferation by targeting telomerase.BackgroundProliferation of SMC during neointima formation is prevented by drug-eluting stents. Although the replicative capacity of mammalian cells is enhanced by telomerase expression, the contribution of telomerase to the proliferative response underlying neointima formation and its potential role as a pharmacological target remain to be investigated.MethodsWe first employed constitutive expression of telomerase reverse transcriptase (TERT) in cell systems to study transcriptional mechanisms by which telomerase activates a mitogenic program. Second, overexpression of telomerase in mice provided a model to study the role of telomerase as a drug target for the antiproliferative efficacy of everolimus.ResultsInhibition of neointima formation by everolimus is lost in mice overexpressing TERT, indicating that repression of telomerase confers the antiproliferative efficacy of everolimus. Everolimus reduces TERT expression in SMC through an Ets-1-dependent inhibition of promoter activation. The inhibition of TERT-dependent SMC proliferation by everolimus occurred in the absence of telomere shortening but rather as a result of a G1→S phase arrest. Although everolimus failed to inhibit phosphorylation of the retinoblastoma protein as the gatekeeper of S-phase entry, it potently repressed downstream target genes. Using chromatin immunoprecipitation assays, we finally demonstrate that TERT induces E2F binding to S-phase gene promoters and supports histone acetylation, effects that are inhibited by everolimus and mediate its antiproliferative activity.ConclusionsThese results characterize telomerase as a previously unrecognized target for the antiproliferative activity of everolimus. Our studies further identify a novel mitogenic pathway in SMC, which depends on the epigenetic activation of S-phase gene promoters by TERT.

Dataset Information

Epigenetic silencing of myogenic gene program by Myb-binding protein 1a suppresses myogenesis.

Publications

Epigenetic silencing of myogenic gene program by Myb-binding protein 1a suppresses myogenesis.

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